Project Summary: Integrated Approach to Close the Loop in Type 1 diabetes We have established in the current grant cycle, that early prandial hyper-glucagonemia is a feature in individuals with type 1 diabetes (T1D) contributing to prandial hyperglycemia. Likewise, plasma glucagon concentrations do not rise appropriately in response to declining glucose concentrations in T1D, placing them at risk for hypoglycemia. However, the causes of these abnormalities are speculated, but not proven to be due to concomitant ? cell dysfunction leading to abnormal glucagon secretion/kinetics. From a network-control view-point, this effect amounts to a disruption of the intra-islet ??? cell feedback control, which we have described in previous work. Therefore, our overarching goal in this application is to apply a novel isotope dilution method we have recently developed, to measure in vivo glucagon kinetics in T1D subjects across clinically relevant scenarios. This will allow quantifying the network deficiencies observed in T1D, and will in turn enable the development of a sophisticated multi-hormonal closed loop artificial pancreas (AP) taking into account the specifics of intra-islet functioning in health and in T1D. At any given time, plasma glucagon concentrations reflect a net balance between the rates of glucagon secretion, its' clearance and it's volume of distribution (VD). Unlike the C-peptide model that is used to measure insulin secretion, no such model is available to measure glucagon kinetics. Hence, it has not been possible to directly and reliably estimate these parameters in humans. Existing control algorithms utilizing glucagon in response to declining glucose concentrations are based on indirect estimations of glucagon kinetics. To directly measure these parameters, we will use novel tracer methods combined with organ catheterization technique, to determine whether, and if so, how glucagon appearance, hepatic extraction, clearance and/or VD is altered in T1D during post absorptive and postprandial states. Thereafter, we will determine systemic glucagon kinetics during subcutaneous (sq) administration of glucagon in T1D, as that is after all, the clinically germane route of administration of glucagon for multi-hormonal AP systems. These data will be used to estimate the parameters of our intra-islet network model and a glucagon secretion model, which will then enable computer simulation and AP algorithm design based on glucagon physiology in T1D. The algorithm will be designed to restore physiological glucagon profiles by using inhibitors of glucagon secretion to prevent excessive early prandial rise in glucagon and subsequent sq. glucagon infusions to restore apt late prandial rise in glucagon levels. Hence, we will build a new system model of glucagon kinetics, endogenous secretion and sq absorption that will be incorporated in an intra-islet network model specific to T1D, and will be then implemented into the FDA approved T1D simulator for in silico testing prior to future multi-hormonal AP clinical trials that will seek to normalize glucose excursions in T1D.